Trk tyrosine kinase receptors are multi-domain single-transmembrane receptors that play an important role in a wide spectrum of neuronal responses including survival, differentiation, growth and regeneration. They are high affinity receptors for neurotrophins, a family of protein growth factors which includes nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophins-4/5 (NT-4/5). NT-3, BDNF and NGF are essential growth factors for the development and maintenance of the nervous system. The neurotrophins are stable homodimers that bind to either or both of two types of cell surface receptors termed p75NTR and Trk.
Mature neurotrophins bind a selective Trk receptor with relatively high affinity (e.g. TrkB-BDNF, TrkA-NGF and TrkC-NT-3). TrkC is the preferred receptor for NT-3 and mediates the multiple effects of NT-3, including neuronal death or survival, and cellular differentiation. The Trk receptor has tyrosine kinase catalytic activity that is associated with the survival and differentiation of neurotrophic signals. Neurotrophin-induced Trk activity affords trophic (growth/survival) responses via MAPK and Akt, whereas PLC-γ and fibroblast growth factor receptor substrate-2 (FRS-2) activity are involved in differentiation.
Trk receptors are widely distributed in the central nervous system and the peripheral nervous system, and play a key role in neuronal survival, differentiation and maintenance of proper function. The relevance of Trk receptor function has been demonstrated in a number of neurodegenerative models, including stroke, spinal cord injury, optic nerve axotomy, glaucoma and amyotrophic lateral sclerosis (ALS). For example, motor neurons express the TrkC receptor, and therefore agents that activate TrkC may be useful for preventing motor neuron degeneration in disorders such as ALS. In addition, Trk receptors have also been implicated in neoplasias, in particular TrkC has been associated with progression in neuroblastoma, medulloblastoma, prostate cancer, and breast cancer. In at least some of these diseases of abnormal cell proliferation, activation of Trk receptors has proven beneficial by induction of tumor death.
A Trk receptor ectodomain termed D5 comprises the main neurotrophin binding site and is required for ligand-dependent receptor activation. Such receptor sites that define ligand-binding and functional-activation are termed “hot spots”. Previously, it has been demonstrated that artificial ligands, such as antibodies, that bind to a receptor hot spot could be functionally active). For example, an agonistic mAb 5C3 directed to a hot spot of the TrkA D5 domain has been reported (LeSauteur et al., 1996, J. Neurosci. 16: 1308-1316).
All mature neurotrophins also bind to p75NTR, while the precursor pro-neurotrophins bind p75NTR exclusively and do not bind Trk receptors. It is known that the p75NTR receptor can affect Trk-binding or function, although the mechanism is not fully understood. It has been shown that p75NTR can unmask a cryptic “hot spot” of Trk receptors, suggesting the notion of allosteric regulation.
ALS is a progressive, fatal, neurodegenerative disease caused by the degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary muscle movement. The disorder causes muscle weakness and atrophy throughout the body as both the upper and lower motor neurons degenerate, unable to send messages to the muscles which then degenerate and atrophy due to their inability to function. ALS is one of the most common neuromuscular diseases worldwide, with one or two out of 100,000 people developing ALS each year. The disease most commonly strikes people between 40 and 60 years of age. ALS is fatal, usually within 3 to 5 years of the onset of symptoms.
Current and prospective treatments for ALS are focused on neuroprotective agents. One of the few available treatments is the neuroprotective agent Riluzole, which is believed to reduce damage to motor neurons by decreasing the release of glutamate, and has been shown to lengthen patient survival by several months. There is presently no cure for ALS. There is a need therefore for new and effective therapies to prevent, inhibit or treat ALS.